PROJECT SUMMARY/ABSTRACT This award will enable Dr. Joaniter Nankabirwa to investigate the impact of indoor residual spraying of insecticides (IRS) alone or in combination with mass drug administration (MDA, administration of a full doses of antimalarial treatment to an entire population irrespective of infection status) on the malaria infectious reservoir, host immunity, and drug resistance. The investigations will leverage data and samples from an on- going study in north-eastern Uganda comparing the community impacts of the interventions on malaria morbidity, mortality and transmission. This work will be undertaken with the guidance of an experienced team of mentors with strong expertise in epidemiology, immunology, molecular microbiology, and the design, implementation and analysis of clinical studies. Dr. Nankabirwa will further her career development by; 1) conducting the laboratory assays, 2) attending courses in clinical research, immunology, molecular microbiology, and data analysis, and 3) attending and presenting at international research conferences. This program will be critical in enabling Dr. Nankabirwa to establish a career as an independent malaria researcher in Uganda. In Uganda, malaria control progress has been slow and control gains have been fragile, with increases in parasite prevalence being observed following cessation of implementation of effective control interventions. For improved control and ultimately elimination, interventions should be designed to eliminate reservoirs of malaria parasites, including microscopic and sub-microscopic infections, and yet minimize both the loss of host immunity, and the development of resistance. The project proposed here will focus on the effects of IRS and MDA on sub-microscopic infections, host immunity and development of resistance, as well as the rebound effects of withdrawing the interventions on these markers. Understanding the impacts of these interventions will help to identify the optimal interventions to control and eliminate malaria in Uganda. We hypothesise that implementing IRS will lead to decreased prevalence of parasite infection, and adding MDA will be associated with a further decrease and sustained reduction in the prevalence, but with some loss of host immunity and increase in drug resistance compared to IRS alone. Findings from this study will guide decision making on how best to implement interventions to control and eliminate malaria in Uganda.